Pulmonary arterial hypertension (PAH) is an uncommon disorder of the pulmonary vasculature characterized by remodeling of the smallest pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance. Various forms of PAH exist, including familial (FPAH) and idiopathic (IPAH) forms and associated conditions. FPAH transmits as an autosomal dominant trait that exhibits genetic anticipation but also markedly reduced penetrance (20%). The primary genetic defect of FPAH, identifiable in more than 70% of cases of FPAH, is a mutation in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor β superfamily. The true prevalence of BMPR2 mutations in IPAH is unknown, with reports ranging from 10% to 40% of patients. The cause of the variable phenotypic expression of PAH among carriers of mutated BMPR2 genes and patients is unclear, and likely related to environmental and genetic modifiers of disease not yet fully elucidated. Although BMPR2-related pathways seem to be pivotal, many other mediator pathways participate in the pathogenesis of different forms of PAH and are being actively investigated, both independently and in combination. As understanding of the molecular basis of this devastating disease improves, opportunities for earlier diagnosis, additional therapeutic regimens, and perhaps disease prevention will emerge.